505(b)(2)

Streamlining Development and
Approval Processes for
505(B)(2) NDAs
Sanjay Sehgal, Ph.D.
Managing Director
Aexelar Regulatory Experts, Inc.
www.aexelar.com
Sept. 5, 2013
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Disclaimer
The information contained in this
presentation are the views and
understanding of the author, Sanjay Sehgal,
and are provided in a scientific discussion
with the understanding that Aexelar Inc. or
any health authority makes no warranties,
either expressed or implied, concerning the
accuracy, completeness, reliability, or
suitability of this information.
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Drug Development,
Review and Approval Processes
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Pharma Industry Revenue Growth
by Major Geographies* (2010 to 2020)
US $$ in Billions (bn)
$1,318bn
$1,081bn
$856bn
505(j) Abbreviated NDA
 505(j) – Abbreviated NDA (ANDA): ANDAs are submitted
for drug products in which the approval of a generic drug
is based on demonstrating comparability to an innovator
drug (RLD) in the US:
 Identical in active ingredients(s)
 Identical in dosage form
 Identical in strength
 Identical in route of administration
 Identical in conditions of use, labeling, performance
 Applications are “abbreviated” as they generally do not
include preclinical or clinical data to establish safety and
efficacy. Instead, they need to demonstrate BE to innovator
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product.
505(b)(1) NDA
 505(b)(1) - Full NDA: An application that contains
complete reports of investigations of safety, effectiveness,
quality of drug product:
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Used for new chemical entities
Studies conducted by the innovator
Requires complete reporting of
• Non-clinical pharmacology/toxicology
• Clinical pharmacology
• Clinical investigations proving safety and efficacy
• Quality (Chemistry, manufacturing, and controls)
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505(b)(2) NDA
 505(b)(2): Intended to encourage innovation in drug
development without requiring duplicative studies (safety,
efficacy) of previously known information (21CFR314.54)
 Applicant must include reports of safety and effectiveness
where at least some of the information required for
approval is from studies “not conducted by or for the
applicant/ sponsor, and for which the applicant has not
obtained a right of reference”
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Not a completely new product
BE to a previously approved product not relevant/required
Documents previously reported non-clinical and clinical data
Approval requires clinical data to support difference(s) and/or
changes to approved products.
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505(b)(2) Business Drivers
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Losses in patent protection in major western markets
$120 billion loss in product revenue during 2010-2015
due to losses in patent protection
Significant competition and growth in generic
pharmaceutical sales
Higher regulatory hurdles, greater uncertainty for
product approval
Declining new (505b1) product approvals
Growing safety and AE reporting requirements by
regulatory agencies
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505(b)(2) NDA Applications
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Change(s) that support submission of a 505(b)(2) NDA
can include:
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Dosage form (e.g. tablets to transdermal patches)
Strengths – higher or lower
Route of administration
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oral to transdermal or iontophoretic delivery
Oral to IV
Immediate release to extended release
Lotion to foam, etc
Dosing regimen
• Twice daily to once a day
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API switch (new salt, ester, complex, racemate,
enantiomer, combinations, etc)
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505(b)(2) NDA Applications
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Change(s) that support submission of a 505(b)(2) NDA
can include (cont’d):
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Formulation changes excluding 505(j)
Substitution of an active ingredient in a combo
product
Different active ingredient (such as a different salt)
Indications – adding new indications
Rx/OTC indication switches
New combination – combining two or more actives
approved individually
Drug-device combination products
Naturally derived or recombinant active ingredient
Bioinequivalence.
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Market Exclusivity - 505(b)(2)
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505(b)(2) applications may be granted exclusivity under
certain conditions:
 3 years Waxman-Hatch exclusivity if one or more of the
clinical investigation(s), other than BA/BE studies, were
conducted or sponsored by the applicant - blocks
approval of other pending 505b2 NDAs regardless of
filing date
 5 years exclusivity if the 505b2 NDA is for a new
chemical entity - blocks filing of competing 505b2
NDAs.
Orphan drug exclusivity possible
Pediatric exclusivity possible.
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Approved 505(b)(2) – 100s; Examples
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Zyrtec D (cetrizine and pseudoephedrine combo) – new
combination product
Zecuity (sumatriptan iontophoretic transdermal system) – new
drug-device combination product
Duraclin (clonoidine) – new formulation and route
Sclerosol (sterile talc) – new molecular entity
Children’s Advil Cold Suspension – new formulation
Methylphenidate Oral Solution – new dosage form
Methylphenidate Chewable Tablets – new dosage form
Doxil (doxorubicin) Liposomal Injection – new dosage form
Altocor (lovastatin) ER Tablets – new dosage form
Vandazole (metronidazole) Vaginal Gel
Forticol (calcitonin-salmon) Nasal Spray
Luxiq Foam (betamethasone) – new delivery tech
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Canasa (mesalamine) Suppositories – new delivery tech.
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505(b)(1)
505(b)(2)
505(b)(2)
combo*
Phases 1-3 development time
5–10 years
2-4 years
2–4 years
Estimated development costs
$800M-$2B
~$10M-$100M
Preclinical/tox data – single and repeat
dose tox data (1 mo, 6 mo, 9 mo)
Always
Usually
Carcinogenicity studies – short, medium
and long term (to 2 yrs)
Always
Usually
Chronic and reproductive tox (6-9 mo),
genotox, local irritation, tolerance studies
Always
Usually
BA and comparative BA data
Always
Always
Pharmacokinetic data – PK, PD data
Always
Always
Clinical trials (Ph I-III) safety and efficacy
data, bridging studies as necessary
Always
Always
API characterization, stability, stressstudies, photo-stability, MLT data
Always
Usually
Drug product stability, stress-studies,
photo-stability, MLT data
Always
Always
FDA Meetings (preIND, EOPII, preNDA)
Always
Usually helpful
10 mo / 6 mo
10 mo (std); 6 mo (priority)
Always
3 or 5 years
Submission Requirements
Approval time period
Exclusivity
*additional requirements for drug-devices
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Streamlining 505(b)(2)
Review and Approval Processes
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Nonclinical summary (Mod 2) and nonclin study reports (Mod 4)
including the following information be reevaluated/eliminated:
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Preclinical/tox data - single and repeat dose (1, 6, 9 mo)
Carcinogenicity data: short, medium, long term (2 yrs)
Chronic dermal tox data
Chronic repeat dermal tox data
Carcinogenicity potential and local tolerance data
Reproductive tox data (6-9 mo), genotox data
API data requirements when an identical API has been approved
previously:
• characterization, stress-studies, photo-stability, MLT data
• API stability data, impurities characterization, etc
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Hold EOPII and pre-NDA/BLA meetings with FDA to align on
submission data, bridging studies, stability data etc.
Given the duplication of information, FDA should consider
shortening the review periods to 6 months for standard and
priority reviews.
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Goal Is To Avoid This At All Costs
NDA
Sponsor
Health
Authority
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